权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Corticostriatal-hypothalamic circuits and opioid seeking

皮质纹状体-下丘脑回路和阿片类药物寻求

基本信息

批准号：
10750717
负责人：
Robin D Vareed
金额：
$ 3.5万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10750717
关键词：
Automobile Driving Behavior Behavior Control Brain Cognitive Therapy Corpus striatum structure Cues Data Down-Regulation Drug Controls Extinction FDA approved Feedback Genetic Heroin Hypothalamic structure Investigation Lateral Measures Medial Modeling Morphine Motivation Neurons Nucleus Accumbens Opioid Output Pathway interactions Pharmaceutical Preparations Pharmacology Population Pre-Clinical Model Prefrontal Cortex Rattus Receptor Activation Recurrence Relapse Rewards Rodent Model Role Schedule Self Administration Severities Site Techniques Therapeutic Therapeutic Effect Therapeutic Intervention Viral Virus addiction antagonist behavior measurement behavioral outcome conditioned place preference drug seeking behavior experimental study feeding genetic manipulation hypocretin innovation learning engagement motivated behavior neural circuit new therapeutic target novel novel strategies novel therapeutic intervention opioid use opioid use disorder optogenetics pharmacologic pre-clinical receptor

项目摘要

PROJECT SUMMARY Opioid use disorder (OUD) is characterized by excessive motivational drive to seek drugs and/or a loss of inhibitory top-down control of drug seeking, resulting in relapse and recurrent drug seeking. Preliminary data from our lab show two opposing circuits originating from the infralimbic (IL) cortex, one that ‘drives’ heroin seeking behavior and one that ‘limits’ heroin seeking behavior. These ‘driver’ and ‘limiter’ pathways project from the IL to subcortical reward and motivational hubs, such as the nucleus accumbens shell (NAsh) and the lateral hypothalamus (LH). Our lab has shown that the ILLH circuit drives heroin seeking and relapse, while the ILNAsh pathway limits heroin seeking. The functional downstream outputs of the ILNAsh limiter pathway are, however, currently unknown. The LH is well characterized as a driver of motivated behavior, and the GABAergic inhibitory projection from the NAshLH projection has been implicated in the suppression of drug seeking behavior after extinction, suggesting inhibition of the LH is a mechanism for decreasing drug seeking. In Aim 1, I will investigate the NAshLH pathway as a potential limiter of heroin seeking, using chemogenetic manipulations to alter activity in this circuit and measure behavioral outcomes on drug seeking in a preclinical model of OUD. I propose that this pathway is an extension of the previously identified ILNAsh limiter pathway, involving an ensemble of neurons in the NAsh that both receive input from the IL and project to the LH. I hypothesize this unique neuronal population will ultimately be responsible for limiting heroin-seeking behavior. The disynaptic ILNAshLH limiter pathway interposes a GABAergic relay between the IL and LH, providing a potential mechanism by which the limiter pathway function is actualized. Thus, it is possible that the disynaptic ILNAshLH limiter circuit and the ILLH driver circuit converge on the LH, where the inhibitory projection from the NAsh may compete with the excitatory projection from the IL to control heroin seeking. Preliminary data from the Peters lab has shown that LH orexin neuron number correlates with metrics of heroin motivation, and systemic blockade of orexin receptors with a dual orexin receptor antagonist (DORA) decreases heroin relapse, strongly implicating the LH orexin neuron population in controlling heroin-seeking behaviors. Further, these LH orexin neurons project to the IL cortex, and blockade of orexin receptors within the IL cortex dampens motivated behaviors. In Aim 2, I will use chemogenetics to determine whether the LHIL pathway drives drug seeking. I will then determine whether intra-IL orexin receptor activation is required for heroin seeking, using brain-site specific pharmacology. If indeed the limiter and driver pathways are competing within the LH, this orexinergic feedback to the IL cortex might be expected to strengthen the driver, leading to an imbalance in heroin seeking. The proposed experiments will identify novel circuits and receptor mechanisms that influence heroin-seeking behavior. It is essential that we further our understanding of the neural circuitry underlying OUD, as these findings will illuminate potential targets for new therapeutic strategies.

项目总结